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Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. In this situation; while obesity cannot be controlled with diet and exercise, it was shown that Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in short term. In this paper, we present our experience with Liraglutide treatment in an adolescent patient carrying MC4R gene variant. A female patient had admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had a marked excess of appetite since infancy. In the physical examination of the pubertal female patient with a body mass index (BMI) of 36.1kg/m2 (3.48 SDS), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss couldn't be achieved with lifestyle changes, metformin and orlistat treatments In genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant (reported previously) was found in the MC4R gene. GLP-1 RA Liraglutide treatment was initiated and a loss of 19.2% reduction was achieved in the patient's body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months after treatment was stopped. In our case carrying a pathogenic variant in the MC4R gene, decrease of appetite and weight loss were achieved with Liraglutide treatment, but this situation could not be maintained. In such cases, there is a need for effective and tolerable treatment options.

Background Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD. Methods Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific sirtuin 6 (SIRT6, 50721) deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo. Results We identified ginsenosides Rc as a novel SIRT6 activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates peroxisome proliferator activated receptor alpha (PPAR-α, 19013)-mediated fatty acid oxidation in vivo and in vitro. Hepatic specific SIRT6 deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD. Conclusion Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving PPAR-α-mediated fatty acid oxidation and antioxidant capacity in a SIRT6 dependent manner, and providing a promising strategy for NAFLD.

Vitamin D (Vit D) insufficiency is caused basically by inadequately sunlight-induced vitamin D in the skin. It is connected to a variety of ongoing illness, especially diabetes type II. Tests have indicated that Vit D is crucial for glucose-induced insulin production and increased insulin impacts. It diminishes insulin resistance and has anti-inflammatory properties. A few reports showed that the destitute eat less, indicating a negative effect on their wellbeing. Insulin resistance is connected to more Vit D levels. Many RCTs in subjects with type II diabetes recognized slight impacts of Vit D on glycemic and insulin resistance. At the same time, these call for more in-depth investigation and the current study is an excellent avenue to start. There is no reason to prescribe Vit D supplementation to avoid or cure type II diabetes mellitus.

Acanthosis Nigricans is considered to be a skin marker of insulin resistance and atherosclerosis. It is rarely reported in cases of insulinoma where there is marked hyperinsulinaemia. We report two cases of insulinoma with acanthosis nigricans which regressed, concomitant with significant weight loss and reduction in blood pressure following surgical resection. This strengthens the hypothesis that hyperinsulinaemia is responsible for Acanthosis nigricans and atherosclerotic risk factors.

A 42 year-old Caribbean woman with, known type 2 diabetes, was admitted with worsening fatigue, arthritis and rashes. She was diagnosed with multisystem systemic lupus erythematosus and was initially treated with systemic steroids. During this admission, she had persistently elevated capillary glucose levels with insulin requirements over 8 U/kg/day that still did not control her blood glucose levels. Due to her profound hyperglycaemia, serum samples of fasting insulin, C-peptide, paired with blood glucose were analysed, which confirmed significant hyperinsulinaemia. Further analysis confirmed the presence of insulin receptor antibodies consistent with type B insulin resistance.She was started on intravenous cyclophosphamide (Euro-Lupus regimen) along with continuous glucose monitoring system. After completing her six cycles of cyclophosphamide, she no longer required insulin treatment. The goal of therapy for our patient with confirmed type B insulin resistance was to manage hyperglycaemia with high doses of insulin until autoantibodies were eliminated with immunosuppressive therapy.

Aim: of this paper is to review the recent literature on the relationship between ectopic fat accumulation and cardiovascular disease. Data synthesis: Ectopic fat is an important predictor of metabolic (in particular insulin resistance) and cardiovascular disease, carrying more risk than general fat accumulation. Recent studies have shown a link between ectopic fat accumulation, as cardiac (epicardial or intra-myocardial fat) and/or visceral and/or hepatic fat, and development of atherosclerosis, coronary heart disease and hypertension. Conclusions: Ectopic fat accumulation is not only a marker of cardiometabolic disease, since through the release of adipocitokines, lipotoxic and glucotoxic agents, participates in the crosstalk with insulin-sensitive organs leading to metabolic, cardiac and vascular dysfunctions., This article version may be used for non-commercial purposes in accordance with CC BY-NC-ND license terms and conditions.

Background: Fatty liver (fatty liver) or Non-lcoholic Fatty Liver Disease (NAFLD) is an excessive accumulation of fat (lipids) in liver cells. Fatty liver is generally associated with metabolic syndrome, obesity, diabetes, and hyperlipidemia. Insulin resistance causes an increase in the entry of Free Fatty Acids (FFA) into the liver and occurs due to the failure of insulin to suppress hormone-sensitive lipases. Basil contains chemical compounds such as phenolic compounds and flavonoids that act as antioxidants that can ward off free radicals. Experimental animals use mice because they have physiological similarities to humans and are easy to keep experimental animals. Purpose: This study aims to determine the effect of basil extract (Ocimum basilicum L.), the effective dose and the duration of the effective dose in reducing SGOT and SGPT levels. Methods Research: The research design used was a descriptive research design. Literature review using the PubMed database and ncbi.mlm.nih.gov using keywords used in data searches to search for journals related to basil extract, SGOT, SGPT, rats, and high-fat diets. Results: The results of the research from 8 journals that have been reviewed found that the levels of SGOT and SGPT had decreased significantly. Basil extract (Ocimum basilicum L.) has been proven preclinically and clinically to reduce AST and ALT levels. Conclusion: The conclusion that can be drawn is that the extract of basil (Ocimum basilicum L.) can reduce levels of SGOT and SGPT. Keywords: Basil Extract, High Fat Diet, NAFLD, SGOT, SGPT, White Rat

Aims To assess lipid trajectories throughout pregnancy in relation to early postpartum glucose intolerance in women with gestational diabetes mellitus (GDM). Methods This prospective cohort study included 221 Chinese women with GDM who completed plasma lipid test in each trimester of pregnancy and oral glucose tolerance test at 6–9 weeks postdelivery between January 1, 2018 and January 8, 2020. Using the group-based trajectory modeling, total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol(HDL-c) were identified separately as three trajectories: low, moderate, and high trajectory. The associations between lipid trajectories and early postpartum glucose intolerance were all evaluated. Results Seventy-three participants developed postpartum glucose intolerance. For patients in low, moderate and high trajectory, the incidence of postpartum glucose intolerance was 38.4%, 34.9%, and 17.9%, respectively. GDM women with lower LDL-c trajectories presented a higher risk of postpartum glucose intolerance. The adjusted odds ratio (95% CI) for glucose intolerance was 3.14 (1.17–8.39) in low LDL-c trajectory and 2.68 (1.05–6.85) in moderate trajectory when compared with the high one. However, TC trajectory was not associated with the risk of postpartum glucose intolerance, nor were TG trajectory and HDL-c trajectory. Moreover, a significant difference of insulin sensitivity was observed in participants with different LDL-c trajectories; participants in high LDL-c trajectory had the highest insulin sensitivity, whereas the women in low LDL-c trajectory had the lowest insulin sensitivity (P = 0.02). Conclusions The high trajectory of LDL-c during pregnancy may play a protective role on postpartum glucose intolerance in women with GDM. Further studies are warranted to explore the underlying mechanism. Trial registration The study was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Sun Yat-sen University (reference number: [2014]No. 93). All participants provided written informed consent forms, and the ethics committee approved this consent procedure.

Background Ginsenoside Rb1 (GRb1) is capable of regulating lipid and glucose metabolism through its action on adipocytes. However, the beneficial role of GRb1-induced up-regulation of adiponectin in liver steatosis remains unelucidated. Thus, we tested whether GRb1 ameliorates liver steatosis and insulin resistance by promoting the expression of adiponectin. Methods 3T3-L1 adipocytes and hepatocytes were used to investigate GRb1's action on adiponectin expression and triglyceride (TG) accumulation. Wild type (WT) mice and adiponectin knockout (KO) mice fed high fat diet were treated with GRb1 for 2 weeks. Hepatic fat accumulation and function as well as insulin sensitivity was measured. The activation of AMPK was also detected in the liver and hepatocytes. Results GRb1 reversed the reduction of adiponectin secretion in adipocytes. The conditioned medium (CM) from adipocytes treated with GRb1 reduced TG accumulation in hepatocytes, which was partly attenuated by the adiponectin antibody. In the KO mice, the GRb1-induced significant decrease of TG content, ALT and AST was blocked by the deletion of adiponectin. The elevations of GRb1-induced insulin sensitivity indicated by OGTT, ITT and HOMA-IR were also weakened in the KO mice. The CM treatment significantly enhanced the phosphorylation of AMPK in hepatocytes, but not GRb1 treatment. Likewise, the phosphorylation of AMPK in liver of the WT mice was increased by GRb1, but not in the KO mice. Conclusions The up-regulation of adiponectin by GRb1 contributes to the amelioration of liver steatosis and insulin resistance, which further elucidates a new mechanism underlying the beneficial effects of GRb1 on obesity.

Abstract. Background: The aim of this study was to assess the effects of supplementation with flaxseed on anthropometric measurements, lipid profile, insulin resistance, and inflammatory biomarkers in overweight and obese adults. Methods: Fifty overweight and obese adults with body mass index (BMI) of 30.72 ± 3.31 kg/m2 participated in this study. Participants were randomly assigned to take lifestyle advice or lifestyle advice plus 30 g/day milled flaxseed for 12 weeks. The primary outcome was body weight; secondary outcomes included other anthropometric parameters, lipid profile and inflammatory biomarkers. Results: At the end of the study, the following significant mean differences were seen in flaxseed and control groups, respectively: weight [−9.36 vs. −3.09 kg; P 2; P Conclusion: These results suggest that flaxseed supplementation in addition to lifestyle modification is significantly superior to lifestyle modification alone for weight loss. More studies with different dosages of flaxseed are needed to find the optimal dosage. This trial was registered at clinicaltrials.gov as NCT02410668.

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P

Introduction This study aimed to investigate the association of diet quality (DQ) and dietary acid load (DAL) with insulin resistance (IR) in overweight children and adolescents. Materials and methods The study was conducted on 135 overweight participants aged 6–17 years. DQ was assessed using the Healthy Eating Index 2015 (HEI-2015) and the HEI-2015-TUBER, revised in accordance with the Turkey Dietary Guidelines (TUBER). Estimation of DAL was made calculating the potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores. Results The HEI-2015-TUBER score was lower in those with IR than in those without IR (p = 0.021). Higher PRAL and NEAP scores were found in those with IR (p = 0.060 and p = 0.044, respectively). Moreover, a one-unit increase in the HEI-2015-TUBER score and the DAL score was associated with a reduction of 4.2% and a rise of approximately 3% in IR risk, respectively. Conclusions Healthy eating habits in overweight paediatric groups may help to reduce the IR risk, improving DQ and decreasing DAL.

Type 2 diabetes mellitus (T2DM) is a progressive meta-inflammatory disorder, which induce micro and macrovascular complications. Resveratrol is a nutraceutical known to have antioxidant and anti-inflammatory properties. It improves insulin resistance; however, no clear evidence regarding its effects in patients with T2DM.We aimed to evaluate the efficacy and the safety of oral resveratrol supplementation in type 2 diabetic patients concerning dose and duration.We searched PubMed, Cochrane Library, Scopus, WOS, Wiley, and Google Scholar for RCTs evaluating the efficacy and safety of resveratrol on patients with T2DM. We screened the studies for the eligibility criteria, performed the quality assessment, extracted the studies' characteristics, baseline, and outcome data of interest, and finally conducted the meta-analysis using RevManV5.3.This systematic review and meta-analysis, including 17 RCTs with total 871 patients with T2DM, showed that resveratrol was superior to placebo on fasting blood glucose (FBG) and total cholesterol (TC) with doses ≥500mg {MD=-13.34, 95%CI [-22.73, -3.95], P=0.005}, {MD=-5.64, 95%CI [-6.95, -4.33], P0.00001} respectively. Moreover, it improved HbA1c at three months {MD=-0.41, 95%CI [-0.65, -0.16], P=0.001 and systolic blood pressure {MD: -7.91, 95%CI [-10.44, -5.37], P0.00001}.We concluded that resveratrol beneficially modulates glycemic control as well as cardiometabolic parameters in patients with T2DM.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

RATIONALE: The effect of insulin resistance on left ventricular function is well documented; however, less is known regarding its effect on the right ventricle (RV). OBJECTIVES: To evaluate the association between insulin resistance and RV function by echocardiography in a cohort of adults without baseline cardiovascular disease. METHODS: We performed a retrospective cohort study in the MESA (Multi-Ethnic Study of Atherosclerosis). Linear regression was used to examine the association between overall insulin resistance measured by the mean triglyceride (TG) to high-density lipoprotein (HDL) cholesterol ratio (TG:HDL) and change in TG:HDL over time for each participant with echocardiographic RV function. Logistic regression was used to calculate the odds ratios (ORs) of RV systolic and diastolic dysfunction. RESULTS: Among 3,032 participants, higher mean TG:HDL was associated with lower (worse) absolute RV longitudinal strain (β, −0.38; 95% confidence interval [CI], −0.64 to −0.13; P

Objective: Pediatric obesity predisposes children and adolescents to early onset insulin resistance and dysglycemia. In the last 20 years this has led to a rise in the prevalence of prediabetes, diabetes and fatty liver in youngsters, due to the high degree of insulin resistance experienced by these patients and the consequent high availability of glucose. As glucose accesses the liver, it is partly metabolized through glycolysis, whose main product is pyruvate that is then converted into Acetyl CoA and lactate. Therefore, lactate production rate (LPR) represents the best proxy for the assessment of glycolysis. Since to date there are not methods to estimate postprandial LPR, here we proposed a novel oral glucose-lactate model to estimate LPR during an oral glucose tolerance test and tested it in 24 youth with and without obesity. Methods: The model is based on the oral glucose minimal model and assumes that LPR is a fraction (fr) of glucose disposal rate, proportional to glucose concentration and controlled by insulin action. Results: The model well fitted the glucose and lactate data, and provided both precise parameter estimates (e.g. fr=22.5 [12.6-54.1]%, median [IQR]), CV=18 [13-25]%) and LPR time course. Conclusions: The proposed model is a valid tool to assess LPR, and thus glycolysis, during OGTT in nondiabetic subjects. Significance: The proposed methodology will allow to assess postprandial LPR in simple and cost-effective way.

Introduction The low-density lipoprotein (LDL)/high-density lipoprotein (HDL) index is a predictive factor for atherosclerosis, which is associated with oxidative modifications. Objective To assess the association of the index with oxidative stress markers. Methods 444 subjects were included and were clinically, anthropometrically and biochemically characterized; superoxide dismutase, glutathione peroxidase 3 (GPx3), magnesium and oxidized LDL (oxLDL) index (oxLDL/HDL) were quantified. Results A decrease of 1.014 units in the LDL/HDL index was associated with a superoxide dismutase increase of 1 unit/mL (p = 0.030), while a decrease of 0.023 units was associated with a GPx3 increase of 1 nmol/min/mL (p < 0.0005). An increase of one unit in the index was associated with an increase of 0.831 in the oxLDL/HDL index (p < 0.05). After controlling for the effect of gender, age, smoking, obesity and insulin resistance, a reduction of 0.001 per index unit was associated with an increase of 1 µg/g of magnesium in the nails (p = 0.020). Conclusions The LDL/HDL index shows an inverse relationship with the antioxidant status and a direct relationship with oxidation status, regardless of other cardiovascular and oxidative stress risk factors.

Aim Diameter, intima-media thickness (IMT), and flow parameters, including resistance index (RI) and pulsatility index (PI), in the common carotid artery (CCA) are markers of arterial remodeling, atherosclerosis, and vascular resistance, respectively. We investigated the differences among these markers in association with plasma glucose level, serum insulin level, and insulin resistance in participants without cardiovascular disease. Methods CCA parameters (including the CCA interadventitial diameter and mean IMT at the time of 75-g oral glucose tolerance testing) were assessed in 4218 participants. RI and PI were assessed in 3380 of these participants. To assess plasma glucose and serum immunoreactive insulin profiles during oral glucose tolerance testing, we used the total areas under the curves (AUCglu and AUCins, respectively). We used the homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda index to assess insulin resistance. Insulin secretion was assessed with the HOMA-β. Results AUCglu was significantly associated with CCA interadventitial diameter (β=0.048, P＜0.001), RI (β=0.144, P＜0.001), and PI (β=0.103, P＜0.001) but not with mean IMT. AUCins (β=-0.064, P＜0.001) and HOMA-β (β=-0.054, P＜0.001) were significantly and negatively associated with CCA interadventitial diameter, but not with mean IMT. Both HOMA-IR and Matsuda index were significantly associated with RI and PI. Conclusions These findings indicate that all CCA parameters except IMT are associated with impaired glucose metabolism in patients without cardiovascular disease.

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, hypertension, insulin resistance, dyslipidemia, and hyperglyemia. MetS is found to be a positive predictor of cardiovascular morbidity and mortality. The present study was planned to test the efficacy of vitamin D3 supplementation as compared with cortisol inhibition on MetS parameters. Wistar rats were allocated into four groups: control, untreated MetS, and MetS treated with either vitamin D3 (10 µg/kg) or carbenoxolone (50 mg/kg). MetS was induced by combination of high-fat diet and oral fructose. After the induction period (8 weeks), MetS was confirmed, and treatment modalities started for a further 4 weeks. Compared with untreated MetS, vitamin D3- and carbenoxolone-treated rats showed significant reduction in blood pressure, body mass index, Lee index, waist circumference, retroperitoneal fat, and improvement of dyslipidemia. Meanwhile, treatment with carbenoxolone significantly lowered the elevated liver enzymes, and vitamin D3 resulted in improved insulin sensitivity, enhanced glucose uptake by muscles, and replenished glycogen content in the liver and muscles near control levels. In conclusion, although treatment with vitamin D3 or carbenoxolone reduced the risk factors associated with MetS, vitamin D3 was effective in ameliorating insulin resistance which is the hallmark of MetS.

Background: Insulin Resistance (IR) is confirmed as a key feature of Nonalcoholic Fatty Liver Disease (NAFLD) in children and adolescents. Numerous studies report that adiponectin (APN) levels are inversely associated with the status of IR in adults with NAFLD. This study aimed to investigate the relationship between serum total APNand Homeostasis Model Assessment Insulin Resistance (HOMA-IR) in adolescents with NAFLD. Methods: 382 newly-diagnosed NAFLD adolescents, aged 9-16 years old, were enrolled and divided into three subgroups according to the APNtertile. Simple and multiple linear regression analyses were performed to assess the correlation between HOMA-IR and APN in boys and girls, respectively. Results: The HOMA-IR values tended to decrease in boys according to APN tertiles: 5.6(4.4-7.3) vs. 5.2(4.6-6.9) vs. 4.9(4.1-5.8) (p Conclusion: Our findings showed that APN was an independent and significant determinant for increased HOMA-IR in boys with NAFLD. Further studies are needed to explore the underlying mechanisms.

Background and aims Nonalcoholic fatty liver disease (NAFLD) is a progressive disease without known effective drug treatments. Switch-associated protein 70 (SWAP70) is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes. However, the role of SWAP70 in NAFLD remains unclear. This study aimed to identify the function and mechanism of SWAP70 in NAFLD. Approach and results The results showed that the expression of SWAP70 was significantly increased in mice and hepatocytes after metabolic stimulation. Overexpression of SWAP70 in hepatocytes suppressed lipid deposition and inflammation, and SWAP70 knockdown created the inverse effect. Using hepatocyte-specific SWAP70 knockout and overexpression mice fed a high-fat, high-cholesterol diet, we demonstrated that SWAP70 suppressed the progression of nonalcoholic steatohepatitis by inhibiting lipid accumulation, inflammatory response and fibrosis. Mechanically, RNA-Seq analysis and immunoprecipitation assays revealed that SWAP70 inhibited the interaction between TAK1 binding protein 1 (TAB1) and transforming growth factor β-activated kinase 1 (TAK1), sequentially suppressed the phosphorylation of TAK1 and subsequent c-Jun-N-terminal kinase (JNK)/P38 signaling. Inhibition of TAK1 activation blocked hepatocyte lipid deposition and inflammation caused by SWAP70 knockdown. Conclusions SWAP70 is a protective molecule that can suppress the progression of NAFLD by inhibiting hepatic steatosis and inflammation. SWAP70 may be important for mitigating the progression of NAFLD.

Fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance that results from an impaired collagen turnover. Peptidase D (PEPD) plays a vital role in collagen turnover by degrading proline-containing dipeptides. Nevertheless, its specific function and importance in AT is unknown. GWAS identified the rs731839 variant in the locus near PEPD that uncouples obesity from insulin resistance and dyslipidaemia, thus indicating that defective PEPD might impair AT remodelling and exacerbate metabolic complications. Here we show that in human and murine obesity, PEPD expression and activity decrease in AT, coupled to the release of PEPD systemically. Both events, in turn, are associated with the accumulation of fibrosis in AT and insulin resistance. Using pharmacologic and genetic animal models of PEPD down-regulation, we show that whereas dysfunctional PEPD activity provokes AT fibrosis, it is the PEPD secreted by AT the main contributor to inflammation, insulin resistance and metabolic dysfunction. Also, PEPD originated in inflammatory macrophages (Mɸ), plays an essential role promoting fibro-inflammatory responses via activation of EGFR in Mɸ and preadipocytes. Using genetic ablation of pepd in Mɸ that prevents obesity-induced PEPD release, also averts AT fibro-inflammation and obesity-associated metabolic dysfunctions. Taking advantage of factor analysis, we have identified the coupling of prolidase decreased activity and increased systemic levels of PEPD as the essential pathogenic triggers of AT fibrosis and insulin resistance. Thus, PEPD produced by Mɸ qualifies as a biomarker of AT fibro-inflammation and a therapeutic target for AT fibrosis and obesity-associated insulin resistance and type 2 diabetes.

To (1) describe the prevalence of cardiometabolic disease (CMD) at spinal cord injury (SCI) rehabilitation discharge; (2) compare this with controls without SCI; and (3) identify factors associated with increased CMD.Multicenter, prospective observational study.Five National Institute on Disability, Independent Living, and Rehabilitation Research Model SCI Rehabilitation Centers.SCI (n=95): patients aged 18-70 years, with SCI (neurologic levels of injury C2-L2, American Spinal Injury Association Impairment Scale grades A-D), and enrolled within 2 months of initial rehabilitation discharge. Control group (n=1609): age/sex/body mass index-matched entries in the National Health and Nutrition Examination Education Survey (2016-2019) (N=1704).None MAIN OUTCOME MEASURES: Percentage of participants with SCI with CMD diagnosis, prevalence of CMD determinants within 2 months of rehabilitation discharge, and other significant early risk associations were analyzed using age, sex, body mass index, insulin resistance (IR) by fasting glucose and Homeostasis Model Assessment (v.2), fasting triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, total cholesterol, and resting blood pressure (systolic and diastolic).Participants with SCI had significantly higher diastolic blood pressure and triglycerides than those without SCI, with lower fasting glucose and HDL-C. A total of 74.0% of participants with SCI vs 38.5% of those without SCI were obese when applying population-specific criteria (P.05). Low HDL-C was measured in 54.2% of participants with SCI vs 15.4% of those without (P.05). IR was not significantly different between groups. A total of 31.6% of participants with SCI had ≥3 CMD determinants, which was 40.7% higher than those without SCI (P.05). Interplay of lipids and lipoproteins (ie, total cholesterol:HDL-C ratio and triglyceride:HDL-C ratio) were associated with elevated risk in participants with SCI for myocardial infarction and stroke. The only significant variable associated with CMD was age (P.05).Individuals with SCI have an increased CMD risk compared with the general population; obesity, IR, and low HDL-C are the most common CMD risk determinants; age is significantly associated with early CMD.

Background and Aim: Subclinical hypothyroidism (SCH) is frequently seen in diabetic patients. Elevated levels of uric acid (UA) were also reported in diabetic patients. No study assessed the relation between SCH and UA levels in diabetic patients. We aimed to evaluate this relation and the association of both conditions with other clinical and laboratory parameters in diabetic patients. Subjects and Methods: This cross-sectional study included 100 T2DM patients in addition to 50 age and sex matched healthy controls. Diabetic patients comprised 50 patients with SCH and 50 euthyroid patients. All participants were subjected to careful history taking, thorough clinical examination and standard laboratory work up. The performed investigations included fasting and postprandial blood sugar, fasting insulin levels, HbA1c levels, thyroid hormones (FT3, FT4 and TSH), renal profile and serum UA. Results: Comparison between the studied groups regarding serum UA levels revealed significantly higher levels in the diabetic group (5.4 ± 1.9 versus 4.2 ± 1.0 mg/dl, p Conclusions: The present study suggests an association between SCH and increased UA levels in diabetic patients.

Aim of the work To assess serum irisin level in rheumatoid arthritis (RA) patients, determine the relationship between irisin levels, disease activity and cardiovascular (CV) risk factors, and to evaluate its performance in predicting subclinical atherosclerosis and disease activity. Patients and methods 60 RA patients and 30 controls were recruited for serological enzyme linked immunosorbant assay (ELISA) testing of irisin levels. Disease activity score (DAS28), health assessment questionnaire disability index (HAD-DI) and American college of rheumatology classification of functional status were assessed. Levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), glycated hemoglobin (HbA1c), insulin and lipid profile were measured. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Carotid intimal medial thickness (C-IMT) was measured and echocardiography performed. Results Serum irisin levels were significantly lower in patients (9.8 ± 10.6 ng/ml) vs. controls (20.5 ± 13.8 ng; p Conclusion In RA, decreased irisin were significantly associated with increased CV risk and performed better than traditional yardsticks in identifying disease activity. It may act as an independent indicator of subclinical atherosclerosis within RA patients.

Objective: Advances in knowledge of neurotrophic factors are now revealing the complex control of energy homeostasis and appetite, as well as the crucial role these factors play in nervous system function. The aim of this study was to assess serum levels of neudesin in adolescents with obesity and to examine the relationship between these levels and metabolic outcomes. Methods: Adolescents, aged 10-17 years were enrolled. Subjects were divided into normal weight, obese and morbidly obese subgroups. Serum neudesin concentrations were compared between the groups. Results: In total, 88 adolescents were recruited, of whom 30 (34.1%) were normal weight, 15 (17.0%) were obese and 43 (48.9%) were morbidly obese. Neudesin levels were significantly lower in obese adolescents than in the control group (p=0.013). A correlation analysis applied to the whole study group revealed a negative correlation between serum neudesin concentration and body mass index (BMI) z scores (r=-0.40, p

The prevalence of obesity is a major cause of many chronic metabolic disorders, including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and cancer. Insulin resistance is often associated with metabolic unhealthy obesity (MUO). Therapeutic approaches aiming to improve insulin sensitivity are believed to be central for the prevention and treatment of MUO. However, current antiobesity drugs are reported as multitargeted and their insulin-sensitizing effects remain unclear. In this review, we discuss current understanding of the mechanisms of insulin resistance from the aspects of endocrine disturbance, inflammation, oxidative, and endoplasmic reticulum stress (ERS). We then summarize the antiobesity drugs, focusing on their effects on insulin sensitivity. Finally, we discuss strategies for obesity treatment.

BACKGROUND/OBJECTIVES: Cirrhosis of liver is associated with loss of liver function, portal hypertension, and pancreatic β-cell dysfunction leading to hepatogenous diabetes (HD). Often HD is an underestimated and understudied problem, particularly in the Indian subcontinent, where the prevalence of both Chronic liver disease (CLD) and diabetes is high. Hence this study was planned to highlight the prevalence of HD and its association with the severity of cirrhosis. METHODS: A total of 121 cirrhotic patients without a history of diabetes were included in this prospective cross-sectional study. Seventy five g oral glucose tolerance test (OGTT) was done in all patients. Fasting serum insulin levels were done to calculate insulin resistance (IR) using homeostatic model assessment-insulin resistance (HOMA-IR). Upper gastrointestinal endoscopy was done to detect varices. Patients were divided into HD group and non-HD group for comparison of results. RESULTS: HD was seen in 52 (42.98%) patients; among them, 63.4% did not show evidence of HD by fasting plasma glucose (FPG) levels. Impaired glucose tolerance (IGT) was seen in 58 (47.93%) patients. Compared with the non-HD group, the HD group had significantly higher model for end-stage liver disease (MELD) score (P = 0.038), HOMA-IR (P 15), CTP score (>10), higher bilirubin levels, large varices, bleeding varices, and HCC. FPG levels and glycated hemoglobin (HbA1c) cannot be relied upon, and OGTT aids in the unmasking of HD in these patients.

Background The aim of obesity treatment is to promote loss of fat relative to lean mass. However, body composition changes with calorie restriction differ among individuals. Objectives The goal of this study was to test the hypothesis that insulin secretion predicts body composition changes among young and middle-age adults with high BMI (in kg/m2) following major weight loss. Methods Exploratory analyses were conducted with pre-randomization data from 2 large feeding trials: the Framingham, Boston, Bloomington, Birmingham, and Baylor study (FB4; n = 82, 43.9% women, BMI ≥27) and the Framingham State Food Study [(FS)2; n = 161, 69.6% women, BMI ≥25]. Participants in the 2 trials consumed calorie-restricted moderate-carbohydrate or very-low-carbohydrate diets to produce 12-18% weight loss in ∼14 wk or 10-14% in ∼10 wk, respectively. We determined insulin concentration 30 min after a 75-g oral glucose load (insulin-30) as a measure of insulin secretion and HOMA-IR as a measure of insulin resistance at baseline. Body composition was determined by DXA at baseline and post-weight loss. Associations were analyzed using general linear models with adjustment for covariates. Results In FB4, higher insulin-30 was associated with a smaller decrease in fat mass (0.441 kg per 100 μIU/mL increment in baseline insulin-30; P = 0.005; -1.20-kg mean difference between the first compared with the fifth group of insulin-30) and a larger decrease in lean mass (-0.465 kg per 100 μIU/mL; P = 0.004; 1.27-kg difference). Participants with higher insulin-30 lost a smaller proportion of weight loss as fat (-3.37% per 100 μIU/mL; P = 0.003; 9.20% difference). Greater HOMA-IR was also significantly associated with adverse body composition changes. Results from (FS)2 were qualitatively similar but of a smaller magnitude. Conclusions Baseline insulin dynamics predict substantial individual differences in body composition following weight loss. These findings may inform understanding of the pathophysiological basis for weight regain and the design of more effective obesity treatment. Registered at clinicaltrials.gov as NCT03394664 and NCT02068885.

Introduction: The study sought to investigate the effect of weight change on hepatic steatosis (HS) incidence with or without liver fibrosis in metabolically healthy overweight or obese individuals. Methods: A cohort of 14,779 metabolically healthy men and women who were overweight or obese (body mass index ≥23 kg/m 2) and free from HS and an intermediate or high probability of fibrosis at baseline were followed for a median of 5.2 years. Metabolic health was defined as freedom from the components of metabolic syndrome and a homeostatic model assessment of insulin resistance 5.0%, relative to the no weight change group (–0.9% to 0.9%) were 0.52 (0.44–0.60), 0.83 (0.75–0.92), 1.21 (1.10–1.33), and 1.51 (1.36–1.69), respectively. Clinically relevant weight loss of >5% was also associated with a lowered risk of HS with intermediate or high probability of advanced fibrosis. In mediation analyses, associations remained significant, although adjustment for metabolic risk factors was attenuating. Discussion: Clinically relevant weight loss was associated with a reduced risk of developing nonalcoholic fatty liver disease with or without intermediate or high probability of advanced fibrosis in metabolically healthy overweight or obese individuals.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age. Insulin resistance is known as the hallmark of PCOS that leads to hyperinsulinemia and type 2 diabetes in PCOS patients. Objective: This study aimed to evaluate the expression pattern of IRS1 as a candidate gene in insulin resistance development in the PCOS rat models. Methods: In this study, estradiol valerate was used for PCOS induction. Then, all of the rats were divided into five experimental groups and treated with Astragalus hamosus extract. Ethanol was used for extraction by Soxhlet, and extracts were analyzed by GC-MS. Ovarian morphology was analyzed using histological experiments. Finally, the expression of IRS1 and hormonal titration of testosterone and insulin were evaluated using qRT-PCR and ELISA assays, respectively. Results: Induction of PCOS led to an increase in body weight, which decreased after treatment with the extract. Histological assessment declared an increased number of corpora lutea in treated groups and reduced cystic follicles compared to the PCOS group. Astragalus hamosus extract-treated groups exhibited decreased levels of insulin and testosterone compared to the PCOS group. qRT-PCR results showed an increase in the expression levels of IRS1 in the treated groups compared to the PCOS group. Conclusions: This study indicated the impact of Astragalus hamosus extract on PCOS by clarifying the increased levels of IRS1 expression in the treated groups compared to the PCOS group.

Background Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in morbid obesity (MO). A considerable proportion of patients with MO have non-alcoholic steatohepatitis (NASH). Liver biopsy (LB) is the only procedure that reliably differentiates NASH from other stages of NAFLD, but its invasive nature prevents it from being generalisable. Hence, non-invasive assessment is critical in this group of patients. Objectives To report NAFLD/NASH prevalence in a cohort of patients with MO and to identify predictors of NASH. Methods Fifty-two consecutive patients subjected to bariatric surgery in a University hospital in Spain underwent LB. Anthropometric, clinical and biochemical variables were registered. According of the results of the LB, individuals were classified by whether they had NASH or not. Multiple logistic regression analysis was performed to identify independent factors associated with NASH. Results NAFLD was reported in 94.2% of the patients, simple steatosis was present in 51.92% and NASH in 42.31%. Meanwhile, 17.3% of patients exhibited significant fibrosis (≥F2). HIGHT score for NASH risk was established using five independent predictors: systemic Hypertension, Insulin resistance, Gamma-glutamyl transferase, High density lipoprotein cholesterol and alanine Transaminase. This score ranges from 0 to 7 and was used to predict NASH in our cohort (area under the receiver operator characteristic curve 0.846). A score of 4 or greater implied high risk (sensitivity 77.3%, specificity 73.3%, positive predictive value 68%, negative predictive value 81.5%, accuracy 75%). Conclusions NAFLD is practically a constant in MO with a considerable proportion of patients presenting NASH. The combination of five independent predictors in a scoring system may help the clinician optimise the selection of patients with MO for LB.

Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs’ disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis. Sustained high circulating levels of fibroblast growth factor (FGF) 21 improve obesity/systemic insulin resistance and promote ketone body production as a second hepatic disposal system for excess free fatty acids. Liver-derived ketone bodies may be utilized for energy in skeletal muscle. The potential FGF21-related crosstalk between the liver and extrahepatic organs is a promising strategy against nonalcoholic fatty liver disease.

The prevalence of metabolic syndrome (MetS) is more common in patients with hypertension and is associated with an increased risk of target organ damage and/or cardiovascular disease (CVD). Omentin-1 is a beneficial adipokine considered to play a role in MetS and MetS-related states such as obesity, diabetes, and coronary artery disease. The aim of this study was to determine the relationship between circulating omentin-1 levels and MetS uncomplicated by diabetes or CVD (nascent MetS) in patients with hypertension. In this study, 110 patients (54 men, 49%; average age: 49.72±11.32 years) treated for hypertension but without overt diabetes and/or CVD were enrolled. 66 patients were stratified into MetS (+) (group 1) and 44 patients into MetS (−) (group 2) according to the American Heart Association/National Heart, Lung, and Blood Institute criteria. The triglyceride glucose (TyG) index was used to assess insulin resistance. Circulating omentin-1 levels in venous blood samples were measured by an ELISA kit. Circulating omentin-1 levels in patients with MetS were significantly lower than in patients without MetS (46.35 ng/mL (42.70–57.70 ng/mL) vs 130.95 ng/mL (62.83–236.48 ng/mL), p

Differentiation of preadipocytes into functional adipocytes could be a major target for repressing obesity-induced insulin resistance (IR). However, the molecular mechanisms involved in adipogenesis and the development of IR are unclear. We report, for the first time, that miR-574-5p, a novel miRNA, promotes adipogenesis to suppress IR. An increase in the level of miR-574-5p significantly induced the differentiation of preadipocytes into mature adipocytes. Conversely, reduction of miR-574-5p levels blocked the differentiation of preadipocytes in vitro. In a dual-luciferase reporter assay, it was shown that homeobox A5 (HOXA5) promoted the transcription of miR-574-5p to induce the differentiation of preadipocytes. Hdac9, a direct downstream target of miR-574-5p, was involved in the regulation of adipocyte differentiation. The overexpression of miR-574-5p also promoted adipogenesis in subcutaneous fat to alleviate IR in high-fat-diet-fed mice. Additionally, miR-574-5p expression was significantly higher in the subcutaneous adipose tissue of obese patients without type 2 diabetes than in those with type 2 diabetes. There was an increase in HOXA5 expression and a decrease in histone deacetylase 9 (HDAC9) expression in the subcutaneous fat of obese patients without type 2 diabetes. These results suggest that miR-574-5p may be a potential therapeutic target for combating obesity-related IR., Graphical abstract, This is the first study to report that the upregulation of the expression of HOXA5-miR-574-5p-HDAC9 axis components can promote adipogenesis and maintenance of subcutaneous adipose expansion to suppress insulin resistance; this could be a potential therapeutic target for combating obesity-related insulin resistance.

Chronic insulin resistance suppresses muscle and liver response to insulin, which is partially due to impaired vesicle trafficking. We report here that a formula consisting of resveratrol, ferulic acid and epigallocatechin-3-O-gallate is more effective in ameliorating muscle and hepatic insulin resistance than the anti-diabetic drugs, metformin and AICAR. The formula enhanced glucose transporter-4 (GLUT4) translocation to the plasma membrane in the insulin-resistant muscle cells by regulating both insulin-independent (calcium and AMPK) and insulin-dependent (PI3K) signaling molecules. Particularly, it regulated the subcellular location of GLUT4 through endosomes to increase glucose uptake under insulin-resistant condition. Meanwhile, this phytochemicals combination increased glycogen synthesis and decreased glucose production in the insulin-resistant liver cells. On the other hand, this formula also showed anti-diabetic potential by the reduction of lipid content in the myotubes, hepatocytes, and adipocytes. This study demonstrated that the three phenolic compounds in the formula could work in distinct mechanisms and enhance both insulin-dependent and independent vesicles trafficking and glucose transport mechanisms to improve carbohydrate and lipid metabolism.

BACKGROUND Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes. METHODS In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed. RESULTS The median plasma XOR activity level was 64.3 pmol/h/mL (33.3-147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055). CONCLUSIONS Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction.

β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein-coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both β-arrestins play key roles in regulating the function of most of these cell types, resulting in striking changes in whole-body glucose and/or energy homeostasis. These studies also revealed that β-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various metabolic disorders, including type 2 diabetes and obesity. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Long-term sleep deprivation (SD) is a bad lifestyle habit, especially among specific occupational practitioners, characterized by circadian rhythm misalignment and abnormal sleep/wake cycles. SD is closely associated with an increased risk of metabolic disturbance, particularly obesity and insulin resistance. The incretin hormone, glucagon-like peptide-1 (GLP-1), is a critical insulin release determinant secreted by the intestinal L-cell upon food intake. Besides, the gut microbiota participates in metabolic homeostasis and regulates GLP-1 release in a circadian rhythm manner. As a commonly recognized intestinal probiotic, Bifidobacterium has various clinical indications regarding its curative effect. However, few studies have investigated the effect of Bifidobacterium supplementation on sleep disorders. In the present study, we explored the impact of long-term SD on the endocrine metabolism of rhesus monkeys and determined the effect of Bifidobacterium supplementation on the SD-induced metabolic status. Lipids concentrations, body weight, fast blood glucose, and insulin levels increased after SD. Furthermore, after two months of long-term SD, the intravenous glucose tolerance test (iVGTT) showed that the glucose metabolism was impaired and the insulin sensitivity decreased. Moreover, one month of Bifidobacterium oral administration significantly reduced blood glucose and attenuated insulin resistance in rhesus macaques. Overall, our results suggested that Bifidobacterium might be used to alleviate SD-induced aberrant glucose metabolism and improve insulin resistance. Also, it might help in better understanding the mechanisms governing the beneficial effects of Bifidobacterium.

The aim of this study was to investigate the relationship between mitochondrial content and respiratory function and whole-body insulin resistance in high-fat diet (HFD) fed rats. Male Wistar rats were given either a chow diet or an HFD for 12 weeks. After 4 weeks of the dietary intervention, half of the rats in each group began 8 weeks of interval training. In vivo glucose and insulin tolerance were assessed. Mitochondrial respiratory function was assessed in permeabilised soleus and white gastrocnemius (WG) muscles. Mitochondrial content was determined by the measurement of citrate synthase (CS) activity and protein expression of components of the electron transport system (ETS). We found HFD rats had impaired glucose and insulin tolerance but increased mitochondrial respiratory function and increased protein expression of components of the ETS. This was accompanied by an increase in CS activity in WG. Exercise training improved glucose and insulin tolerance in the HFD rats. Mitochondrial respiratory function was increased with exercise training in the chow-fed animals in soleus muscle. This exercise effect was absent in the HFD animals. In conclusion, exercise training improved insulin resistance in HFD rats but without changes in mitochondrial respiratory function and content. The lack of an association between mitochondrial characteristics and whole-body insulin resistance was reinforced by the absence of strong correlations between these measures. Our results suggest that improvements in mitochondrial respiratory function and content are not responsible for improvements in whole-body insulin resistance in HFD rats.

Background and Objective: Subclinical hypothyroidism can potentially develop into overt hypothyroidism. Thyroid hormones have substantial roles in metabolism and glucose homeostasis and thus, are closely related to determinant factors of metabolic syndromes, such as obesity and insulin resistance. Osteocalcin is considered a predictor of metabolic conditions in thyroid diseases. This study aimed to investigate the effect of levothyroxine vs. placebo on serum osteocalcin levels in patients with subclinical hypothyroidism. Methods: This randomized clinical trial was performed on 30 patients with subclinical hypothyroidism, who were referred to the endocrine clinics of Ghaem and Imam Reza hospitals in Mashhad, Iran. After giving informed consent, patients were randomly divided into intervention (50 μg/- day levothyroxine for 2 months) and control (placebo) groups. Serum levels of osteocalcin, thyroid hormones, lipid profile, insulin, and fasting glucose, as well as other clinical and anthropometric data, were measured at baseline and at the end of the study. SPSS was used to analyze the data, and p < 0.05 was considered significant. Results: Mean age in the intervention and control groups was 35.07 ± 9.94 and 31.30 ± 4.30, respectively (p = 0.20). There was no significant difference between osteocalcin levels before and after the intervention in either of the groups (p = 0.54). TSH level was significantly decreased in the levothyroxine group after the intervention (p < 0.01). T4 level was significantly increased in the intervention group (p = 0.02). Conclusion: Levothyroxine had no significant effect on the increasing levels of serum osteocalcin in patients with subclinical hypothyroidism. Clinical Trail Registration Code: We have registered the trial in the Iranian Registry of Clinical Trials (IRCT) with the registration code IRCT20171129037677N1.

Intake of dietary antioxidants is inversely associated with reduced markers of atherosclerosis development such as carotid intima-media thickness (CIMT).This study was designed to assess the effects of selenium supplementation on CIMT and metabolic profiles of in diabetic hemodialysis (HD) patients.This randomized, double-blind, placebo-controlled trial was performed on 60 diabetic HD patients. Subjects were randomly assigned to receive selenium supplements or placebo (starch). Individuals in the selenium group (n = 30) received 200 μg selenium per day in the placebo group (n = 30) received for 24 weeks. Fasting blood samples were taken at the study baseline and after 24 weeks of intervention.Following the administration of selenium supplements, was observed a significant reduction in serum insulin levels (P = 0.003), insulin resistance (P = 0.003), total cholesterol (P = 0.008), LDL-cholesterol (P 0.001) and C-reactive protein (CRP) (P 0.001), and a significant increase in insulin sensitivity (P 0.001), HDL-cholesterol (P 0.001) and total glutathione (GSH) (P 0.001) compared with the placebo.Selenium supplementation in diabetic HD patients had beneficial effects on markers of insulin metabolism, total-, LDL-, HDL-cholesterol, CRP and GSH levels. This trial was registered at www.irct.ir as http://www.irct.ir: IRCT20170513033941N47.

Obesity, an epidemic metabolic disease characterized by excessive fat accumulation, causes a significant economic burden on families and the society. The discovery of beige adipocytes has provided us with a brand new approach for the intervention of obesity 1 . Beige adipocytes increase energy expenditure and improve the balance of glucose and lipid metabolism. Reduction of beige adipocytes is a hallmark of obesity. Mechanism underlying the decrement of beigeing remains largely unknown. Intestinal microflora is strongly associated with white adipose tissue beigeing. Removal of intestinal microflora with antibiotic treatment or germ-free mice can effectively promote beigeing of subcutaneous and visceral adipose tissue 2 . However, it is still unclear how the intestinal microflora influences white adipose tissue beigeing. Previous studies have suggested that bacterial products may affect the thermogenesis of white and brown adipose tissue 3 . For example, lipopolysaccharides (LPS) from Gram-negative bacteria have been reported to suppress adaptive thermogenesis 4 . However, studies have shown an increase in the ratio of Gram-positive firmicutes to Gram-negative bacteroidetes 5 . These observations suggest that products of intestinal Gram-positive bacterial may also contribute to modulation of beigeing. Peptidoglycan (PGN) is a unique and essential structural element in the cell wall of Gram-positive bacteria. It is embedded in a relatively thick cell wall with other polymers, such as lipoteichoic acids (LTAs). Our previous study suggests that PGN plays an important role in insulin resistance and metabolic inflammation 6 . Whether PGN affects the beigeing of adipose tissue remains unclear. PGNs from diverse bacteria function through Toll-like receptor (TLR) 2 to activate multiple signaling such as NFκB and JNK. As a critical molecule in innate immune response 7 , TLR2 may be involved in diet-induced metabolic syndrome. TLR2 deficiency improves insulin sensitivity, beta cell dysfunction and hepatic insulin signaling in mice 8 . It remains unclear whether the beneficial effects of TLR2 deficiency occur indirectly by suppressing inflammatory cells in metabolic tissues or directly by acting on parenchymal cells. Here we reported that PGN suppresses the white adipose tissue beigeing. This occurs through induction of inflammation in adipose tissue by promoting macrophage M1 polarization. In addition, PGN directly activates TLR2 receptor on adipocytes to suppress beigeing. Intervention of PGN-TLR2 signaling may thus provide a potential strategy for treatment of obesity.

Summary Background & Aims Creatine supplementation shows promising effects on diabetes, especially in glucose management and insulin secretion. This study aimed to review the literature on studies that evaluated the effects of creatine supplementation on parameters of diabetes in humans. Methods We conducted a systematic review and meta-analysis, until December 2020, in the following databases: Pubmed, Lilacs, Scielo, Scopus, SPORTDiscus, Web of Science, Embase, and Cochrane. It included experimental studies that investigated the effects of creatine supplementation on diabetes treatment or prevention and its relationship with fasting blood glucose and insulin resistance. Results Nine studies were included in the review, from which five showed some benefit of creatine supplementation in at least one diabetes parameter. In diabetic individuals (n = 2), creatine was beneficial. In the meta-analysis, there are no significant effect on fasting blood glucose [SMD: 0.05; CI95%: -0.53, 0.63; p = 0.28; I2 = 22%] and insulin resistance [SMD: -0.38; 95% CI: -0.90, 0.14; p = 0.22; I2 = 33%]. Conclusion Our results demonstrated an insufficient basis to state that creatine can positively affect diabetes parameters. Future studies should be conducted with diabetic individuals due to the potential of creatine on diabetes parameters.

Global rates of obesity and type 2 diabetes mellitus (T2DM) are increasing globally concomitant with a rising prevalence of sleep deprivation and sleep disorders. Understanding the links between sleep, obesity and T2DM might offer an opportunity to develop better prevention and treatment strategies for these epidemics. Experimental studies have shown that sleep restriction is associated with changes in energy homeostasis, insulin resistance and β-cell function. Epidemiological cohort studies established short sleep duration as a risk factor for developing obesity and T2DM. In addition, small studies suggested that short sleep duration was associated with less weight loss following lifestyle interventions or bariatric surgery. In this article, we review the epidemiological evidence linking sleep duration to obesity and T2DM and plausible mechanisms. In addition, we review the impact of changes in sleep duration on obesity and T2DM.

Insulin resistance is one of the earliest pathological features of a suite of diseases including type 2 diabetes collectively referred to as metabolic syndrome. There is a growing body of evidence from both pre-clinical studies and human cohorts indicating that reactive oxygen species, such as the superoxide radical anion and hydrogen peroxide are key players in the development of insulin resistance. Here we review the evidence linking mitochondrial reactive oxygen species generated within mitochondria with insulin resistance in adipose tissue and skeletal muscle, two major insulin sensitive tissues. We outline the relevant mitochondria-derived reactive species, how the mitochondrial redox state is regulated, and methodologies available to measure mitochondrial reactive oxygen species. Importantly, we highlight key experimental issues to be considered when studying the role of mitochondrial reactive oxygen species in insulin resistance. Evaluating the available literature on both mitochondrial reactive oxygen species/redox state and insulin resistance in a variety of biological systems, we conclude that the weight of evidence suggests a likely role for mitochondrial reactive oxygen species in the etiology of insulin resistance in adipose tissue and skeletal muscle. However, major limitations in the methods used to study reactive oxygen species in insulin resistance as well as the lack of data linking mitochondrial reactive oxygen species and cytosolic insulin signaling pathways are significant obstacles in proving the mechanistic link between these two processes. We provide a framework to guide future studies to provide stronger mechanistic information on the link between mitochondrial reactive oxygen species and insulin resistance as understanding the source, localization, nature, and quantity of mitochondrial reactive oxygen species, their targets and downstream signaling pathways may pave the way for important new therapeutic strategies.

Background: High blood insulin levels, insulin resistance (IR), and obesity are components of metabolic syndrome (MetS). The literature has indicated a high risk of breast cancer in patients with M...

Inhalation of fine particulate matter (PM2.5), produced by the combustion of fossil fuels, is an important risk factor for cardiovascular disease. Exposure to PM2.5 has been linked to increases in blood pressure, thrombosis, and insulin resistance. It also induces vascular injury and accelerates atherogenesis. Results from animal models corroborate epidemiological evidence and suggest that the cardiovascular effects of PM2.5 may be attributable, in part, to oxidative stress, inflammation, and the activation of the autonomic nervous system. Although the underlying mechanisms remain unclear, there is robust evidence that long-term exposure to PM2.5 is associated with premature mortality due to heart failure, stoke, and ischemic heart disease. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Мета дослідження: вивчити клінічну ефективність та безпечність препарату Армадин® у ранньому відновному періоді гострого ішемічного інсульту, його вплив на відновлення втрачених функцій та постінсультну втому в пацієнтів із метаболічним синдромом (МС). Особливістю роботи було визначення стратегічних ділянок мозку за даними магнітно-резонансної томографії (МРТ) при когнітивних та емоційних розладах у пацієнтів з ішемічним інсультом на фоні МС та порівняння з даними пацієнтів без МС. Матеріали і методи. Основну групу становили 28 пацієнтів віком від 44 до 79 років (у середньому 66,0 ± 4,2 року), які знаходились у ранньому відновному періоді ішемічного інсульту. Пацієнти основної групи крім базового лікування отримували Армадин®. Контрольну групу становили 16 хворих у ранньому відновному періоді ішемічного інсульту віком від 54 до 76 років (середній вік 63,0 ± 3,8 року), які отримували лише стандартне лікування. Стан пацієнтів оцінювали за шкалами NIHSS, Ренкіна, індексом Бартел. Когнітивний і емоційний стан — за шкалами HADS, MMSE. Кількісну оцінку постінсультної втоми проводили за шкалою оцінки втоми (FAS). МРТ-дослідження головного мозку виконувалось на апараті Siemens MAGNETOM Avanto 1.5T. Визначали розміри вогнищ, індекс гіпокампу. Результати. Патологічна постінсультна втома визначалась в обох групах: медіана вираженості втоми за опитувальником FAS становила 32,2 (Q1 = 16,5; Q3 = 51,5) в основній та 34,25 (Q1 = 14,5; Q3 = 48,5) у контрольній групі до лікування. У 95 % пацієнтів визначалась клінічно значима втома (FAS ≥ 22), а ознаки депресії (вираженої та помірної) мали близько 20 %. Не було визначено статистично вірогідної кореляційної залежності патологічної втоми й депресії. Патологічна втома за шкалою FAS була вірогідно більшою в жінок, ніж у чоловіків. Після проведеного лікування ознаки патологічної втоми зменшились за шкалою FAS в обох групах, але статистичної вірогідності досягли в групі, що додатково приймала Армадин®. За шкалою NIHSS та індексом Бартел вірогідне покращення після лікування визначалось серед хворих основної групи. Не було визначено залежності між вираженістю патологічної втоми за шкалою FAS і ступенем тяжкості інсульту за шкалою NIHSS. Покращення показників когнітивних функцій за період лікування визначалось в обох групах. Але в основній групі когнітивні функції покращились на 5 %, а в групі контролю — на 1,66 %. За методикою, що була запропонована Scheltens et al., виконано дослідження гіпокампу на 1,5 Tл МРТ у пацієнтів з МС (перша група) і пацієнтів без МС (друга група). У пацієнтів із МС визначалось вірогідне зменшення індексу гіпокампу праворуч і ліворуч порівняно з пацієнтами без МС: праворуч 0,50 [0,41; 0,54] проти 0,594 [0,58; 0,61] (р < 0,05); ліворуч 0,56 [0,52; 0,60] проти 0,61 [0,58; 0,63] (р < 0,05). Обговорення. Своєчасне діагностування патологічної постінсультної втоми має велике значення в лікуванні хворих з ішемічним інсультом. У нашому дослідженні патологічна втома була діагностована в 95,5 % хворих. Різниця з літературними даними, ймовірно, пов’язана з наявністю кластера МС у пацієнтів, які брали участь у дослідженні. Досить невелика кількість пацієнтів унеможливлює висновок про вплив МС на розвиток патологічної втоми. Слід враховувати, що патологічна втома може розвинутись і без депресії і вона потребує спеціального лікування без залучення антидепресантів. Покращення когнітивних функцій та зменшення проявів астенії в пацієнтів, які приймали Армадин®, ймовірно, можна пояснити, з одного боку, здатністю Армадину® підвищувати рівень дофаміну в головному мозку, а з іншого — наявністю у складі Армадину® янтарної кислоти, що сприяла, через ланцюг нейрохімічних реакцій, підвищенню в головному мозку рівня ГАМК. Отже, використання цього сучасного антиоксиданту сприяло зменшенню астенії й тим самим покращувало якість життя пацієнтів. Вимірювання гіпокампу показало вірогідно більше виражену атрофію в пацієнтів з ішемічним інсультом на фоні МС порівняно з показниками пацієнтів з ішемічним інсультом без МС (P < 0,05). Ймовірно, кластер МС, що поєднує артеріальну гіпертензію, інсулінорезистентність, дисліпідемію та ін., прискорює атрофічні процеси гіпокампу більше, ніж окремо кожний з цих компонентів, які визначали у пацієнтів з ішемічним інсультом без МС. Висновки. Призначення Армадину® в ранньому відновному періоді ішемічного інсульту сприяло зменшенню проявів патологічної втоми в пацієнтів з МС, відновленню функцій за шкалою NIHSS і індексом Бартел.